EP2310033B1 - Peptide compounds for treating amyloidoses - Google Patents

Peptide compounds for treating amyloidoses Download PDF

Info

Publication number
EP2310033B1
EP2310033B1 EP09761152A EP09761152A EP2310033B1 EP 2310033 B1 EP2310033 B1 EP 2310033B1 EP 09761152 A EP09761152 A EP 09761152A EP 09761152 A EP09761152 A EP 09761152A EP 2310033 B1 EP2310033 B1 EP 2310033B1
Authority
EP
European Patent Office
Prior art keywords
peptide
compound
amino acid
acid sequence
peptides
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP09761152A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2310033A2 (en
Inventor
Markus Mandler
Radmila Santic
Harald Weninger
Edith Kopinits
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Affiris AG
Original Assignee
Affiris AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Affiris AG filed Critical Affiris AG
Publication of EP2310033A2 publication Critical patent/EP2310033A2/en
Application granted granted Critical
Publication of EP2310033B1 publication Critical patent/EP2310033B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to the prevention and treatment of diseases associated with ß-amyloid formation and/or aggregation (ß-Amyloidoses). More particularly, the present invention provides new mimotopes eliciting an immune response directed against ⁇ -amyloid and N-terminally truncated and/or posttranslationally modified ß-amyloid fragments and new-antibodies recognizing said mimotopes and Aß peptides for use in the prevention, treatment and diagnosis of diseases associated with ß-amyloid formation and/or aggregation.
  • ß-Amyloidoses diseases associated with ß-amyloid formation and/or aggregation
  • ß-amyloidoses Various degenerative diseases are characterized by the aberrant polymerization and accumulation of specific proteins so called proteopathies.
  • the present invention relates to the prevention, treatment and diagnosis of proteopathies associated with ß-amyloid proteins summarised under the term ß-amyloidoses.
  • the most prominent form of ß-amyloidoses is Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • Other examples include but are not limited to Dementia with Lewy bodies and Dementia in Down syndrome.
  • AD Alzheimer's disease
  • a ⁇ Amy-loin- ⁇
  • APP Amyloid Precursor Protein
  • APP is normally processed by two cleavage steps to form the currently known forms of Abeta x-40/42/43.
  • the first cleavage is performed by the so called beta-site APP-cleaving enzymes 1 and 2 (BACE1 and BACE2) ; the second proteolytic step is performed by the gamma-Secretase Complex.
  • BACE enzymes recognise two sites in the N-terminal portion of the presumptive A ⁇ peptide and proteolytic acitivity of BACE leads to the formation of Abeta 1-X and 11-X respectively.
  • BACE mediated APP processing creates a variety of different Aß species with full length Abeta 1-40/42 as major contribuent.
  • Gamma-Secretase activity leads to production of 3 main fragments: Aß 1-40/42/43.
  • Amino-peptidases resulting in their subsequent stepwise degradation.
  • alpha-Secretase family The third family of proteolytic enzymes involved in APP processing is the so called alpha-Secretase family (ADAM ('a disintegrin and metalloprotease') family.
  • Alpha secretases cleave amyloid precursor protein (APP) in its transmembrane region (between aa16 and aa17 of the Aß peptide sequence) and preclude the formation of Aß peptides.
  • alpha Secretase cleavage is the crucial step for non-amyloidogenic APP processing.
  • alpha secretases cleavage results in release of a secreted form called sAPPalpha.
  • sAPPalpha is considered to be sufficient to mediate most of physiological functions of APP and may serve as a signalling molecule.
  • sAPP was found to be neuroprotective for primary neurons in culture, preventing elevations in intracellular Ca2+ levels caused by glucose deprivation and raising the excitotoxic threshold of glutamate, as well as mediating axonal and dendritic growth.
  • amyloid plaque material is formed by Aß40/42 derivatives which are N-terminally truncated and frequently modified.
  • the relative amounts of N-terminally truncated Aß species are variable in respect of Aß levels, mutations and BACE activity.
  • the most abundant truncated forms of Aß are: A ⁇ -40/42 and A ⁇ 11-40/42 thought to constitute up to 50% of all truncated forms. This means that these isoforms constitute 25-40 % of all amyloid peptides in AD brains.
  • Both peptides contain an N-terminal glutamate residue, which is frequently modified enzymatically to pyro-glutamate, resulting in the formation of A ⁇ 3 (pE) -40/42 and A ⁇ 11 (pE) -40/42, respectively. Because the amino terminus of the Abeta 3(pE) and 11(pE) peptides is blocked by internal lactam, it is protected from the proteolytic action of aminopeptidases other than pyroglutamate-specific ones and can thus remain stable in tissues. Additional N-terminally truncated amyloid variants starting at position 2, 3, 4, 5, 6, 7, 8, 9, or 10 of beta amyloid can be detected in AD patients. These forms are frequently post translationally modified, e.g. by methylation.
  • Truncated forms of A ⁇ can already be detected in diffuse aggregations of A ⁇ in early stages of AD and might be involved in early plaque formation, acting as individual seeds in vivo.
  • a ⁇ x-40/42 peptides may initiate and/or accelerate plaque formation, perhaps by acting as nucleating centers that seed the subsequent deposition of relatively less amyloidogenic but apparently more abundant full-length A ⁇ peptides.
  • N-terminally truncated A ⁇ species is correlated with increasing severity and early onset of neurodegeneration in sporadic and familial Alzheimer disease as well as Down Syndrome patients. Data from such patients are implying a link between early formation of truncated A ⁇ species and disease onset, as well as progression.
  • AD-vaccine should thus elicit an immune response which is able to target the most prominent forms of A ⁇ peptides present in the brain of AD patients, A ⁇ 1-40/42, Aß3-40/42 as well as A ⁇ 3(p)E-40/42 and Aß11-40/42 as well as Aß11(p)E-40/42 without interfering with physiological functions of APP signalling, notably the functions of sAPPalpha.
  • the present invention relates to the use of at least one compound comprising the amino acid sequence (X 1 ) m HX 2 X 3 X 4 X 5 FX 6 (X 7 ) n (Formula II), wherein
  • the invention presented herein refers to antigens which do not contain sequences of the native A ⁇ peptide but are however mimicking the structure of neo-epitopes of Aß not detectable by Mimotopes such as described in the WO 2004/062556 .
  • Such a Mimotope-based AD vaccine therefore induces antibody responses exclusively reacting with the pathological A ⁇ molecules mentioned above but not with parental structures.
  • the immune response induced by these Mimotopes does not interact with full length APP and secreted APPalpha (sAPPalpha) and thus the vaccination retains normal physiologic functions of both molecules.
  • Mimotopes do not contain potential T-cell self-epitopes and avoid induction of detrimental autoreactive T-cells.
  • a compound comprising an amino acid sequence of the formula I is able to induce the in vivo formation of antibodies which are directed to the non truncated A ⁇ form A ⁇ 1-40/42, and N-terminally truncated forms like A ⁇ 3-40/42, Aß(pE)3-40/42, unmodified Aß11-40/42, modified Aßp(E)11-40/42 and Aß14-40/42, respectively, and also to further N-terminally truncated and posttranslationally modified amyloid variants starting at position 2, 4, 5, 6, 7, 8, 9, or 10 of Aß.
  • these mimotopes do not induce a cross reactivity to the neoepitopes present in sAPP alpha after cleavage from APP and thus do not interfere with normal sAPP alpha signalling.
  • the antibodies formed by the vaccination of the molecules (mimotopes) of the present invention are able to bind to the A ⁇ fragments listed above resulting in the disintegration of A ⁇ plaques.
  • Formula I and II and all other peptidic molecules disclosed herein mimick the natural occurring Aß peptides and variants Aß1-40/42, AßpE3-40/42, Aß3-40/42 and Aß11-40/42, AßpE11-40/42 and Aß14-40/42 so that compounds comprising the amino acid sequences disclosed herein are able to induce the formation of respective antibodies. Additional N-terminally truncated and posttranslationally modified amyloid variants starting at position 2, 4, 5, 6, 7, 8, 9, or 10 of Aß can be detected by such antibodies as well.
  • ß-Amyloidoses refers to various degenerative diseases which are characterized by the aberrant polymerization and accumulation of specific proteins so called proteopathies.
  • the present invention relates to the prevention, treatment and diagnosis of proteopathies associated with ß-amyloid proteins summarized under the term ß-amyloidoses.
  • the most prominent form of ß-Amyloidoses is Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • Other examples include but are not limited to Dementia with Lewy bodies and Dementia in Down syndrome.
  • Lewy body dementia myositis, sporadic inclusion body myositis, hereditary cerebral hemorrhage with amyloidosis (Dutch type), cerebral amyloid angiopathy, Aß related angiitis.
  • the compound comprises a peptide having an amino acid sequence selected from the group consisting of SHTRLYF(C), HMRLFFN(C), SHQRLWF(C), HQKMIFA(C), HMRMYFE(C), THQRLWF(C) and HQKMIF(C), preferably from the group consisting of SHTRLYF(C), HMRLFFN(C), HQKMIFA(C), HMRMYFE(C), THQRLWF(C) (all of which are able to induce in vivo the formation of antibodies directed to A ⁇ peptides).
  • SHTRLYF(C), HMRLFFN(C), SHQRLWF(C), HQKMIFA(C), HMRMYFE(C), THQRLWF(C) preferably from the group consisting of SHTRLYF(C), HMRLFFN(C), HQKMIFA(C), HMRMYFE(C), THQRLWF(C) (all of which are able to induce in vivo the
  • the at least one compound comprises a peptide having amino acid sequence SHTRLYF(C), SGEYVFH(C), SGQLKFP(C), SGQIWFR(C), SGEIHFN(C), HMRLFFN(C), GELWFP(C), HQKMIFA(C), GEIWFEG (C), GEIYFER(C), THQRLWF(C), GEIRFGS(C), GEIKFDH(C) or GEIQFGA(C), in particular HQKMIFA(C).
  • Another aspect of the present invention relates to the use of at least one compound comprising the amino acid sequence (X 1 ) m GX 2 X 3 X 4 FX 5 X 6 (X7) n (Formula I), wherein
  • the compound comprises a peptide having an amino acid sequence selected from the group consisting of SGEYVFH(C), SGQLKFP(C), SGQIWFR(C), SGEIHFN(C), GQIWFIS(C), GQIIFQS(C), GQIRFDH(C), GEMWFAL(C), GELQFPP(C), GELWFP(C), GEMQFFI(C), GELYFRA(C), GEIRFAL(C), GMIVFPH(C), GEIWFEG(C), GDLKFPL(C), GQILFPV(C), GELFFPK(C), GQIMFPR(C), GSLFFWP(C), GEILFGM(C), GQLKFPF(C), GTIFFRD(C), GQIKFAQ(C), GTLIFHH(C), GEIRFGS(C), GQIQFPL(C), GEIKFDH(C), GEYVFH(C), SG
  • Particularly preferred compounds of the present invention comprise or consist of the above identified amino acid sequences, whereby the C-terminus of said peptide may or may not comprise a cysteine residue (indicated by the use of brackets) so that the compound obtained may be coupled, e.g., to a carrier molecule.
  • a cysteine residue indicated by the use of brackets
  • the amino acid sequence is selected from the group consisting of GELWFP(C), GEIWFEG(C), GEIYFER(C), GEILFGM(C), GEIKFDH(C), GEIQFGA(C) (all of which are competing peptides) and GEIKFDH(C), GEIRFGS(C), SGQLKFP(C), SGQIWFR(C), SGEIHFN(C), GELWFP(C), GEIWFEG(C), GEIYFER(C), GEIQFGA(C), SGEYVFH(C) (all of which are able to induce in vivo the formation of antibodies directed to A ⁇ peptides listed above).
  • Another aspect of the present invention relates to the use of at least one compound comprising an amino acid sequence selected from the group consisting of AIPLFVM(C), KLPLFVM(C), QLPLFVL(C) and NDAKIVF(C) for producing a medicament for preventing and/or treating Alzheimer's disease.
  • Each of the compounds of the present invention is able to induce the in vivo formation of antibodies directed to peptides derived from A ⁇ 40/42 including A ⁇ 1-40/42, and N-terminally truncated forms like Aß3-40/42, Aß(pE)3-40/42, unmodified Aß11-40/42, modified Aßp(E)11-40/42 and Aß14-40/42, respectively. Since the compounds of the present invention are isolated by an antibody which is directed to amino acid residues 14 to 19 of A ⁇ , the compounds of the present invention are able to induce the formation of antibodies which can bind to truncations of the A ⁇ peptide starting from amino acid position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 of the A ⁇ peptides.
  • these compounds are particularly well suited to treat and/or prevent AD because the administration of at least one of said compounds results in the formation of antibodies which are capable to recognize the major Aß forms, e.g. Aß1-40/42, AßE3-40/42 and Aß3-40/42.
  • These mimotopes furthermore fail to induce a cross reactivity to the neoepitopes present in sAPP alpha after cleavage from APP and thus do not interfere with normal sAPP alpha signalling.
  • the compounds of the present invention in particular the peptides of the present invention may further be modified at their N-terminus by an acylation and/or acetylation reaction.
  • a particularly preferred compound comprises the amino acid sequence AC-GEIYFER(C).
  • the term "mimotope” refers to a molecule which has a conformation that has a topology equivalent to the epitope of which it is a mimic.
  • the mimotope binds to the same antigen-binding region of an antibody which binds immunospecifically to a desired antigen.
  • the mimotope will elicit an immunological response in a host that is reactive to the antigen to which it is a mimic.
  • the mimotope may also act as a competitor for the epitope of which it is a mimic in in vitro inhibition assays (e.g. ELISA inhibition assays) which involve the epitope and an antibody binding to said epitope.
  • a mimotope of the present invention may not necessarily prevent or compete with the binding of the epitope of which it is a mimic in an in vitro inhibition assay although it is capable to induce a specific immune response when administered to a mammal.
  • epitope refers to an immunogenic region of an antigen which is recognized by a particular antibody molecule.
  • an antigen will possess one or more epitopes, each capable of binding an antibody that recognizes the particular epitope.
  • the mimotopes of the present invention can be synthetically produced by chemical synthesis methods which are well known in the art, either as an isolated peptide or as a part of another peptide or polypeptide.
  • the peptide mimotope can be produced in a microorganism which produces the peptide mimotope which is then isolated and if desired, further purified.
  • the peptide mimotope can be produced in microorganisms such as bacteria, yeast or fungi, in eukaryote cells such as a mammalian or an insect cell, or in a recombinant virus vector such as adenovirus, poxvirus, herpesvirus, Simliki forest virus, baculovirus, bacteriophage, Sindbis virus or sendai virus.
  • Suitable bacteria for producing the peptide mimotope include E.coli, , B.subtilis or any other bacterium that is capable of expressing peptides such as the peptide mimotope.
  • Suitable yeast types for expressing the peptide mimotope include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida, Pichia pastoris or any other yeast capable of expressing peptides. Corresponding methods are well known in the art. Also methods for isolating and purifying recombinantly produced peptides are well known in the art and include e.g. as gel filtration, affinity chromatography, ion exchange chromatography etc..
  • a fusion polypeptide may be made wherein the peptide mimotope is translationally fused (covalently linked) to a heterologous polypeptide which enables isolation by affinity chromatography.
  • Typical heterologous polypeptides are His-Tag (e.g. His 6 ; 6 histidine residues), GST-Tag (Glutathione-S-transferase) etc..
  • His-Tag e.g. His 6 ; 6 histidine residues
  • GST-Tag Glutathione-S-transferase
  • the fusion polypeptide may comprise a cleavage site at the junction between the peptide mimotope and the heterologous polypeptide.
  • the cleavage site consists of an amino acid sequence that is cleaved with an enzyme specific for the amino acid sequence at the site (e.g. proteases).
  • the mimotopes of the present invention may also be modified at or nearby their N- and/or C-termini so that at said positions a cysteine residue is bound thereto.
  • terminally positioned (located at the N- and C-termini of the peptide) cysteine residues are used to cyclize the peptides through a disulfide bond.
  • the mimotopes of the present invention may also be used in various assays and kits, in particular in immunological assays and kits. Therefore, it is particularly preferred that the mimotope may be part of another peptide or polypeptide, particularly an enzyme which is used as a reporter in immunological assays.
  • reporter enzymes include e.g. alkaline phosphatase or horseradish peroxidase.
  • the mimotopes according to the present invention preferably are antigenic polypeptides which in their amino acid sequence vary from the amino acid sequence of A ⁇ or of fragments of A ⁇ .
  • the inventive mimotopes may not only comprise amino acid substitutions of one or more naturally occurring amino acid residues but also of one or more non-natural amino acids (i.e. not from the 20 "classical” amino acids) or they may be completely assembled of such non-natural amino acids.
  • inventive antigens which induce antibodies directed and binding to Aß1-40/42, A ⁇ pE3-40/42, Aß3-40/42, Aß11-40/42, AßpE11-40/42 and Aß14-40/42 may be assembled of D- or L- amino acids or of combinations of DL- amino acids and, optionally, they may have been changed by further modifications, ring closures or derivatizations.
  • Suitable antibody-inducing antigens may be provided from commercially available peptide libraries.
  • these peptides are at least 7 amino acids, and preferred lengths may be up to 16, preferably up to 14 or 20 amino acids (e.g. 5 to 16 amino acid residues). According to the invention, however, also longer peptides may very well be employed as antibody-inducing antigens.
  • the mimotopes of the present invention may also be part of a polypeptide and consequently comprising at their N- and/or C-terminus at least one further amino acid residue.
  • peptide libraries are suitable, for instance produced by means of combinatorial chemistry or obtained by means of high throughput screening techniques for the most varying structures ( Display: A Laboratory Manual by Carlos F. Barbas (Editor), et al.; Willats WG Phage display: practicalities and prospects. Plant Mol. Biol. 2002 Dec.; 50(6):837-54 ).
  • anti-Aß1-40/42--AßpE3-40/42-, -Aß3-40/42-, -Aß11-40/42- AßpE11-40/42- and Aß14-40/42-antibody-inducing antigens based on nucleic acids may be employed, and these, too, may be found with the most varying (oligonucleotide) libraries (e.g. with 2-180 nucleic acid residues) (e.g. Burgstaller et al., Curr. Opin. Drug Discov. Dev. 5(5) (2002), 690-700 ; Famulok et al., Acc. Chem. Res.
  • the nucleic acid backbone can be provided e.g. by the natural phosphor-diester compounds, or also by phosphorotioates or combinations or chemical variations (e.g. as PNA), wherein as bases, according to the invention primarily U, T, A, C, G, H and mC can be employed.
  • the 2'-resides of the nucleotides which can be used according to the present invention preferably are H, OH, F, Cl, NH 2 , O-methyl, O-ethyl, O-propyl or O-butyl, wherein the nucleic acids may also be differently modified, i.e. for instance with protective groups, as they are commonly employed in oligonucleotide synthesis.
  • aptamer-based antibody-inducing antigens are also preferred antibody-inducing antigens within the scope of the present invention.
  • the compound is coupled to a pharmaceutically acceptable carrier, preferably KLH (Keyhole Limpet Hemocyanin), tetanus toxoid, albumin-binding protein, bovine serum albumin, a dendrimer (MAP; Biol. Chem. 358: 581), peptide linkers (or flanking regions) as well as the adjuvant substances described in Singh et al., Nat. Biotech. 17 (1999), 1075-1081 (in particular those in Table 1 of that document), and O'Hagan et al., Nature Reviews, Drug Discovery 2 (9) (2003), 727-735 (in particular the endogenous immuno-potentiating compounds and delivery systems described therein), or mixtures thereof.
  • KLH Keyhole Limpet Hemocyanin
  • tetanus toxoid albumin-binding protein
  • bovine serum albumin bovine serum albumin
  • MAP dendrimer
  • peptide linkers or flanking regions
  • the conjugation chemistry e.g. via heterobifunctional compounds such as GMBS and of course also others as described in "Bioconjugate Techniques", Greg T. Hermanson
  • the vaccine composition may be formulated with an adjuvant, preferably a low soluble aluminium composition, in particular aluminium hydroxide.
  • adjuvants like MF59 aluminium phosphate, calcium phosphate, cytokines (e.g., IL-2, IL-12, GM-CSF), saponins (e.g., QS21), MDP derivatives, CpG oligos, LPS, MPL, polyphosphazenes, emulsions (e.g., Freund's, SAF), liposomes, virosomes, iscoms, cochleates, PLG microparticles, poloxamer particles, virus-like particles, heat-labile enterotoxin (LT), cholera toxin (CT), mutant toxins (e.g., LTK63 and LTR72), microparticles and/or polymerized liposomes may be used.
  • cytokines e.g., IL-2, IL-12, GM-CSF
  • saponins e.g., QS21
  • MDP derivatives e.g., CpG oligo
  • the compound of the present invention is preferably bound to the carrier or adjuvant via a linker, which is selected from the group consisting of NHS-poly (ethylene oxide) (PEO) (e.g. NHS-PEO 4 -maleimide).
  • a linker which is selected from the group consisting of NHS-poly (ethylene oxide) (PEO) (e.g. NHS-PEO 4 -maleimide).
  • a vaccine which comprises the present compound (mimotope) and the pharmaceutically acceptable carrier may be administered by any suitable mode of application, e.g. i.d., i.v., i.p., i.m., intranasally, orally, subcutaneously, etc. and in any suitable delivery device ( O'Hagan et al., Nature Reviews, Drug Discovery 2 (9), (2003), 727-735 ).
  • the compound of the present invention is preferably formulated for intravenous, subcutaneous, intradermal or intramuscular administration (see e.g. " Handbook of Pharmaceutical Manufacturing Formulations", Sarfaraz Niazi, CRC Press Inc, 2004 ).
  • the medicament (vaccine) according to the present invention contains the compound according to the invention in an amount of from 0.1 ng to 10 mg, preferably 10 ng to 1 mg, in particular 100 ng to 100 ⁇ g, or, alternatively, e.g. 100 fmol to 10 ⁇ mol, preferably 10 pmol to 1 ⁇ mol, in particular 100 pmol to 100 nmol.
  • the vaccine may also contain auxiliary substances, e.g. buffers, stabilizers etc.
  • Another aspect of the present invention relates to the use of a compound as defined above for treating and/or ameliorating symptoms of synucleopathy.
  • the compounds of the present invention can also be used to treat and ameliorate symptoms associated with synucleopathies.
  • Amyloidoses and synucleopathies are associated with the cerebral accumulation of ⁇ -amyloid and ⁇ -synuclein, respectively. Some patients show clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways. These patients are also classified as suffering from a newly identified syndrome described as Dementia with Lewy Bodies or Parkinson's disease with dementia (DLB/PDD).
  • DLB/PDD Parkinson's disease with dementia
  • the treatment approach presented in the current invention is describing an immunotherapy targeting Aß which will lead to the removal of mainly extracellular amyloid. It is thus believed to relieve the amyloid associated alterations ranging from plaque deposition to neuronal death as well as to memory problems and cognitive decline.
  • the subcellular localization of synucleins however indicates that these intracellular proteins are mainly active at the synapse, especially confined to synaptic vesicles.
  • synuclein accumulations which are the unifying pathologic hallmark of synucleopathies, are mainly detectable intracellularly.
  • synucleopathies are believed to be attributable to intraneuronal changes ranging from mitochondrial dysfunction, accumulation of abnormally folded, ubi-quitinated or phosphorylated proteins as well as accumulation of alpha synuclein. These alterations are consequently resulting in changes in synaptic functions, synaptic failure, and loss of dopaminergic neurons and classical clinical signs of synucleopathies.
  • Aß is mainly detectable extraneuronally and amyloid plaques as well as fibrils, protofibrils and oligomers of beta amyloid can exert neurotoxic functions when applied extracellularly or intracerebrally.
  • the term "synucleinopathy” includes all neurodegenerative disorders characterized by pathological synuclein aggregations.
  • Several neurodegenerative disorders including Parkinson's Disease (PD), Lewy Body Disease (LBD), Diffuse Lewy Body Disease (DLBD); Dementia with Lewy Bodies (DLB), Parkinsonism with Dementia (PDD), Multiple System Atrophy (MSA) and Neurodegeneration with Brain Iron Accumulation type I (NBIA Type I) are collectively grouped as synucleinopathies.
  • Symptoms of synucleopathy refers to those symptoms of the synucleopathies, in particular Parkinson's disease, which affect the motor and non-motor behaviour of a patient suffering from said disease.
  • “Motor symptoms” include resting tremor, Bradykinesia, rigidity, postural instability, stooped posture, dystonia, fatigue, impaired fine motor dexterity and motor coordination, impaired gross motor coordination, poverty of movement (decreased arm swing), akathisia, speech problems, such as softness of voice or slurred speech caused by lack of muscle control, loss of facial expression, or "masking", micrographia, difficulty swallowing, sexual dysfunction, drooling etc.
  • “Non-motor” symptoms include pain, dementia or confusion, sleep disturbances, constipation, skin problems, depression, fear or anxiety, memory difficulties and slowed thinking, urinary problems, fatigue and aching, loss of energy, compulsive behaviour, cramping etc.
  • the synucleopathy is selected from the group of Parkinson's Disease, Dementia with Lewy Bodies, multiple system atrophy and neurodegeneration with brain iron accumulation. Particularly preferred is Parkinson's disease.
  • Another aspect of the present invention relates to a peptide having or consisting of an amino acid sequence selected from the group consisting of SHTRLYF(C), SGEYVFH(C), SGQLKFP(C), SGQIWFR(C), SGEIHFN(C), GQIWFIS(C), NDAKIVF(C), GQIIFQS(C), GQIRFDH(C), HMRLFFN(C), GEMWFAL(C), GELQFPP(C), GELWFP(C), SHQRLWF(C), HQKMIFA(C), GEMQFFI(C), GELYFRA(C), GEIRFAL(C), GMIVFPH(C), GEIWFEG(C), GEIYFER(C), AIPLFVM(C), GDLKFPL(C), GQILFPV(C), GELFFPK(C), GQIMFPR(C), HMRMYFE(C), GSLFFWP(C), GEIL
  • the peptides of the present invention may or may not comprise the cysteine residue at the Cor N-terminus. Consequently the present invention encompasses also the following amino acid sequences: SHTRLYF, SGEYVFH, SGQLKFP, SGQIWFR, SGEIHFN, GQIWFIS, NDAKIVF, GQIIFQS, GQIRFDH, HMRLFFN, GEMWFAL, GELQFPP, GELWFP, SHQRLWF, HQKMIFA, GEMQFFI, GELYFRA, GEIRFAL, GMIVFPH, GEIWFEG, GEIYFER, AIPLFVM, GDLKFPL, GQILFPV, GELFFPK, GQIMFPR, HMRMYFE, GSLFFWP, GEILFGM, GQLKFPF, KLPLFVM, GTIFFRD, THQRLWF, GQIKFAQ, GTLIF
  • the peptide is coupled to a pharmaceutically acceptable carrier, preferably KLH (Keyhole Limpet Hemocyanin).
  • a pharmaceutically acceptable carrier preferably KLH (Keyhole Limpet Hemocyanin).
  • Yet another aspect of the present invention relates to a pharmaceutical formulation, preferably a vaccine, comprising at least one peptide according to the present invention.
  • Said pharmaceutical formulation may be employed to treat individuals suffering from Alzheimer's disease or prevent the formation of A ⁇ -plaques in an individual to impede the formation of Alzheimer's disease.
  • the antibodies used for the mimotope identification according to the present invention detect amino acid sequences derived from human Aß but do not bind to full length human APP.
  • the antibody may be a monoclonal or polyclonal antibody preparation or any antibody part or derivative thereof, the only prerequisite is that the antibody molecule specifically recognises at least one of the epitopes mentioned above (derived from human Aß), but does not bind to full length human APP.
  • the mimotopes are identified and further characterised with such monoclonal antibodies and peptide libraries.
  • Example 1 Generation of monoclonal antibodies to specifically detect ß -amyloid and N-terminally truncated and / or posttranslationally modified ß -amyloid fragments.
  • a monoclonal antibody derived from the fusion of experiment Alz-9 was generated: C57/B16 mice were immunized repeatedly with original Aß epitope HQKLVFC coupled to KLH (Keyhole Limpet Hemocyanin) and Alum (Aluiminium Hydroxide) as adjuvant. p4377 peptide-specific, antibody-producing hybridomas were detected by ELISA (p4377-peptide-coated ELISA plates). Human A ⁇ 40/42 (recombinant protein) was used as positive control peptide: hybridomas recognizing the recombinant protein immobilised on ELISA plates were included because they were binding both peptide and full length A ⁇ specifically.
  • p1454 Human Aß 33-40 was used as negative control peptide. Furthermore hybridomas were tested against p4374, p1323 and sAPP-alpha. Only hybridomas with good p4374, and p1323 binding and a lack of sAPP-alpha binding were used for further antibody development.
  • the Hybridoma clone MV-002 (internal name A115; IgG2b) was purified and analysed for specific detection of p1323, p4374, p4377, p1454, Aß and sAPP-alpha respectively.
  • MV-002 recognized the epitopes p1323 as well as p4377 and full length Aß protein (recombinant protein; obtained from Bachem AG, Bubendorf, Switzerland) in ELISA. It however did not detect p1454 in ELISA.
  • the MV-002 antibodies failed to detect sAPP-alpha but bound specifically to the peptide p4374 encoding the pyroglutamate version of Aß11-19.
  • Phage Display libraries used in this example were: Ph.D. 7: New England BioLabs E8102L (linear 7mer library). Phage Display was done according to manufacturer's protocol ( www.neb.com ).
  • Peptides derived from Phage Display as well as variants thereof were coupled to BSA and bound to ELISA plates (1 ⁇ M; as indicated in the respective figures) and subsequently incubated with the monoclonal antibody that was used for the screening procedure to analyse binding capacity of identified peptides.
  • Example 3 in vivo testing of mimotopes: analysis of immunogenicity and crossreactivity
  • Inhibiting as well as non-inhibiting peptides were coupled to KLH and injected into mice (wildtype C57/B16 mice; subcutaneous injection into the flank) together with an appropriate adjuvant (aluminium hydroxide). Animals were vaccinated 3-6 times in biweekly intervals and sera were taken biweekly as well. Titers to injected peptides, as well as to an irrelevant peptide were determined with every serum. Furthermore, titers against the recombinant human A ⁇ protein, and against original peptides were determined respectively. In general sera were analysed by reaction against peptides coupled to Bovine Serum Albumin (BSA) and recombinant full length proteins which were immobilised on ELISA plates. Titers were determined using anti mouse IgG specific antibodies. For detailed results see Figures 4 , 5 and 6 respectively.
  • BSA Bovine Serum Albumin
  • Figure 1 depicts the characterisation of the monoclonal antibody MV-002 (internal name A115; IgG2b) derived from experiment Alz-9 demonstrating specificity for full length Aß and Aß fragments truncated at position E11 and H14 and modified at position E11 to pE11.
  • GEILFGMC 3 p4690 30 GQLKFPFC 3 p4691 31 KLPLFVMC 1 p4692 32 GTIFFRDC 1 p4693 33 THQRLWFC 3 p4694 34 GQIKFAQC 3 p4695 35 GTLIFHHC 2 p4696 36 GEIRFGSC 3 p4697 37 GQIQFPLC 3 p4698 38 GEIKFDHC 3 p4699 39 GEIQFGAC 3 p4700 40 QLPLFVL 1 p4794 41 HQKMIFC 2 p4795 42 GELFFEKC 2 p4796 43 GEIRFELC 2 p4804 44 Ac-GEIYFERC 2 p4805 45 SGEIYFERC 1 p4806 46 AGEIYFERC 1 p4807 47 CGEIYFER 1 Legend to Table 1: the binding capacity is coded by the following binding code: 1:X describes the dilution factor of the parental AB. Ac-...indicates acetylated
  • FIGS 2 and 3 show representative examples for binding and inhibition assays used to characterise mimotopes in vitro. Data obtained are summarised in Tables 1 and 2 respectively.
  • MV-002 Mimotopes From the 47 sequences presented 11 sequences inhibited binding of the monoclonal antibody MV-002 in in vitro competition experiments. Additional 36 sequences were identified that did not inhibit binding of monoclonal antibody in in vitro competition experiments but still retained binding capacity to the parental antibody (Table 2). Importantly, as described in Figures 4-6 , the ability to compete with the original epitope for binding to the parental antibody in vitro was no prerequisite to mount specific immune responses cross reacting with specific peptides in vivo.
  • inhibiting as well as non-inhibiting peptides can be used for inducing immune responses detecting peptides in vivo (for details see: Figures 4-6 ) which can lead to clearance of amyloid peptides from the brain.
  • Table 2 mimotopes identified in this invention giving positive results in inhibiting assays; MV-002 Mimotopes Internal Peptide number SEQ ID No.
  • Mimotopes are compared to the original peptide as standard. OD at 5ug peptide used in the assay is used to calculate the competition capacity compared to original peptide.
  • competition code 0 no inhibition (OD of peptide above 4,6 times of original peptide) 1 Weaker than original epitope (OD of peptide below 4, 6 times of original peptide) 2 strong inhibition (as original epitope; OD of peptide below 2,3 times of original peptide)
  • mice Female C57/b16 mice, 5-6 mice per group, were subcutaneously immunized with 30 ⁇ g peptide coupled to KLH. Control groups were administered original epitope-KLH conjugates respectively. As adjuvant alum was used (always 1 mg per mouse). The peptides administered were all able to bind to monoclonal antibodies specifically although some of the peptides did not inhibit the binding of the original epitope to its parental antibody in vitro (in an in vitro inhibition assay). The in vitro ELISA assay to determine the antibody titer was performed with sera of single mice after each vaccination in a two week interval (see Fig. 6 and 7 respectively). Titers were calculated as OD max/2 in all figures shown.
  • FIGS. 4 , 5 and 6 show representative examples for assays used to characterise mimotopes in vivo. The results depicted were derived from peptides active in in vitro inhibition assays like p4670, p4675, p4680, and p4681 and a peptide without inhibition capacity, p4403 respectively.
  • Figure 4 shows examples for in vivo characterisations of the immune response elicited by mimotope vaccination by analysing the immune response against injected peptide and an irrelevant peptide, containing an unrelated sequence.
  • the epitope p4377 and the mimotopes p4670, p4675, p4680, p4681 and p4403 elicited immune responses against the injected peptides but failed to induce a relevant unspecific immune response against an unrelated sequence (p1454).
  • Figure 5 shows examples for in vivo characterisations of the immune response elicited by mimotope vaccination against the respective original epitope of the parental antibody (p4377) as well as against peptides derived from truncated species of Aß (p1323 and p4374) and against sAPP alpha.
  • the mimotopes p4670, p4675, p4680, p4681 and p4403 mounted detectable immune responses against the original epitope p4377.
  • a similar phenomenon could be detected analysing cross reactivity against the modified form as displayed by p4374.
  • the original epitope and the mimotope vaccines mounted relevant titers against p4374 the modified form of the original epitope.
  • the mimotopes seemed to be able to induce but did not necessarily induce a more efficient immune response against p1323 indicating a potential to induce a broader immuno-reactivity as compared to the original Aß fragment. Additionally, no reactivity was detectable against sAPP alpha.
  • Figure 6 shows examples for in vivo characterisations of the immune response elicited by mimotope vaccination against full length Aß.
  • the mimotopes selected by using MV-002 induced a cross reaction not only with the truncated or modified short epitopes used to create the antibodies but also induced cross reactivity to full length, non modified forms of Aß as good as the original sequence or even more efficiently than p4377.
  • competing as well as non competing peptides were able to induce similar immune responses specifically interacting with peptides containing original Aß sequences.
  • the mimotopes presented in this invention constitute optimised, novel vaccine candidates to target a broad spectrum of naturally occurring forms of the Aß peptides as have been found in the brain of AD patients.
  • the forms include but are not limited to Aß1-40/42, and N-terminally truncated forms like Aß3-40/42, Aß(pE)3-40/42, unmodified Aß11-40/42, modified Aßp(E)11-40/42 and Aß14-40/42 respectively.
  • the mimotopes presented also did not induce a cross reactivity to the neoepitopes present in sAPP alpha after cleavage from APP and thus do not interfere with normal sAPP alpha signalling (see Figure 5 for details).
  • the Tg2576 AD mouse model was used to study the preclinical efficacy of the mimotope vaccines.
  • This transgenic line is expressing human APP carrying the Swedish double mutation at aa position 670/671 under the control of a hamster prion protein (PrP) promoter which results in overexpression of the protein.
  • PrP hamster prion protein
  • the Tg2576 model recapitulates various hallmarks of AD pathology including disease-specific amyloid plaque deposition and astrocytosis. As all other AD model systems available to date, it does not reflect all cardinal neuropathological features of AD.
  • mice were s.c. injected 6 times at monthly intervals with peptide-KLH conjugates adsorbed to ALUM (adjuvant: aluminium hydroxide) or PBS adsorbed to ALUM (referred to as PBS or control) alone.
  • ALUM adjuvant: aluminium hydroxide
  • PBS adsorbed to ALUM
  • animals were sacrificed, their brains harvested and analyzed for their Aß load (AD-like pathology). The mice were sacrificed under deep anaesthesia. Subsequently, the brain was isolated, fixed in 4%PFA and dehydrated by graded Ethanol series followed by incubation in Xylene and paraffin embedding. Each paraffin-embedded brain was sectioned at 7 ⁇ M using a slicing microtome and sections were mounted on glass slides.
  • this set of data clearly indicates a beneficial effect of mimotope vaccine treatment on AD like pathology in transgenic animals.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
EP09761152A 2008-06-12 2009-06-12 Peptide compounds for treating amyloidoses Active EP2310033B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0095208A AT506820B1 (de) 2008-06-12 2008-06-12 Vakzine gegen alzheimer-krankheit
PCT/AT2009/000235 WO2009149485A2 (en) 2008-06-12 2009-06-12 Compounds for treating amyloidoses

Publications (2)

Publication Number Publication Date
EP2310033A2 EP2310033A2 (en) 2011-04-20
EP2310033B1 true EP2310033B1 (en) 2012-09-05

Family

ID=41401983

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09761152A Active EP2310033B1 (en) 2008-06-12 2009-06-12 Peptide compounds for treating amyloidoses

Country Status (14)

Country Link
US (1) US8409581B2 (enrdf_load_stackoverflow)
EP (1) EP2310033B1 (enrdf_load_stackoverflow)
JP (3) JP2011522840A (enrdf_load_stackoverflow)
KR (1) KR20110036039A (enrdf_load_stackoverflow)
CN (1) CN102123728B (enrdf_load_stackoverflow)
AT (2) AT506820B1 (enrdf_load_stackoverflow)
AU (1) AU2009257168B2 (enrdf_load_stackoverflow)
BR (1) BRPI0915136A2 (enrdf_load_stackoverflow)
CA (1) CA2723967A1 (enrdf_load_stackoverflow)
ES (1) ES2392789T3 (enrdf_load_stackoverflow)
IL (1) IL209894A (enrdf_load_stackoverflow)
MX (1) MX2010013657A (enrdf_load_stackoverflow)
RU (1) RU2491953C2 (enrdf_load_stackoverflow)
WO (1) WO2009149485A2 (enrdf_load_stackoverflow)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120328605A1 (en) * 2010-10-27 2012-12-27 Daniel Larocque Compositions and uses
CN103459421B (zh) * 2011-03-16 2017-07-14 前体生物药物股份公司 诊断性抗体测定
GB201113570D0 (en) 2011-08-05 2011-09-21 Glaxosmithkline Biolog Sa Vaccine
PL2579042T3 (pl) 2011-10-04 2014-12-31 Affiris Ag Sposób wykrywania przeciwciał swoistych wobec Aß w próbce biologicznej
EP2659908A1 (en) 2012-05-01 2013-11-06 Affiris AG Compositions
US9102752B2 (en) * 2013-03-15 2015-08-11 United Biomedical, Inc. Peptide vaccine for prevention and immunotherapy of dementia of the Alzheimer's type
EP2787347A1 (en) 2013-04-03 2014-10-08 Affiris AG Method for detecting Aß-specific antibodies in a biological sample
CN106535924A (zh) * 2014-04-29 2017-03-22 阿费里斯股份公司 阿尔茨海默病(ad)的治疗和预防
WO2015165961A1 (en) 2014-04-29 2015-11-05 Affiris Ag Treatment and prevention of alzheimer's disease (ad)
CA2946931A1 (en) 2014-04-29 2015-11-05 Affiris Ag Treatment and prevention of alzheimer's disease (ad)
AU2016353553B2 (en) 2015-11-09 2022-01-20 The University Of British Columbia Amyloid beta epitopes and antibodies thereto
CA3004482A1 (en) 2015-11-09 2017-05-18 Neil R. Cashman N-terminal epitopes in amyloid beta and conformationally-selective antibodies thereto
EP3374381A4 (en) 2015-11-09 2019-05-15 The University Of British Columbia EPITOPES IN THE AMYLOID-BETA MEDIUM REGION AND CONFORMITY-SELECTIVE ANTIBODIES THEREOF
AU2017299858B2 (en) 2016-07-18 2024-07-25 Promis Neurosciences, Inc. Antibodies to Amyloid beta
US20180125920A1 (en) 2016-11-09 2018-05-10 The University Of British Columbia Methods for preventing and treating A-beta oligomer-associated and/or -induced diseases and conditions
WO2019014768A1 (en) 2017-07-18 2019-01-24 The University Of British Columbia ANTI-BETA-AMYLOID ANTIBODY
US12286469B2 (en) 2017-07-18 2025-04-29 The University Of British Columbia Humanized antibodies binding to amyloid-beta (A-beta)
RU2679080C1 (ru) * 2018-04-17 2019-02-05 Александр Олегович Морозов Пептид и способ лечения болезни альцгеймера
CN115925987A (zh) * 2022-02-28 2023-04-07 安域生物科技(杭州)有限公司 基于β-淀粉样蛋白修饰的抗原多肽及其应用
CN119136838A (zh) 2022-02-28 2024-12-13 特瑞德姆生物科技有限责任两合公司 由至少一种β-葡聚糖或甘露聚糖组成或包含至少一种β-葡聚糖或甘露聚糖的偶联物

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780587A (en) * 1990-08-24 1998-07-14 President And Fellows Of Harvard College Compounds and methods for inhibiting β-protein filament formation and neurotoxicity
US7964192B1 (en) * 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
EP1075270B1 (en) * 1998-04-06 2005-06-15 Advanced Immunit, Inc. Short peptide for treatment of neurological degenerative diseases
NO314086B1 (no) * 1998-05-08 2003-01-27 Gemvax As Peptider og farmasöytiske sammensetninger inneholdende disse, nukleinsyresekvenser som koder for slike peptider, plasmider og virusvektoreromfattende slike DNA-sekvenser samt anvendelse av disse for fremstilling avfarmasöytiske preparater til
CA2325600A1 (en) * 1998-05-21 1999-11-25 The University Of Tennessee Research Corporation Methods for amyloid removal using anti-amyloid antibodies
US7504490B1 (en) * 1998-10-16 2009-03-17 Oscient Pharmaceuticals Corporation Nucleic acid and amino acid sequences relating to Apergillus fumigatus for diagnostics and therapeutics
US20040067535A1 (en) * 2002-10-03 2004-04-08 Life Sciences Development Corp. Alzheimer's disease linked genes
CN1753662A (zh) * 2002-12-24 2006-03-29 神经化学（国际）有限公司 用于治疗β－淀粉状蛋白相关疾病的治疗制剂
AT413945B (de) * 2003-01-14 2006-07-15 Mattner Frank Dr Impfstoff für die alzheimer-krankheit
EP1440981A3 (en) * 2003-01-21 2005-11-23 Research Association for Biotechnology Full-length human cdna
US7358331B2 (en) * 2003-05-19 2008-04-15 Elan Pharmaceuticals, Inc. Truncated fragments of alpha-synuclein in Lewy body disease
AT500483B1 (de) * 2004-07-13 2006-01-15 Mattner Frank Dr Set zur vorbeugung oder behandlung der alzheimer'schen erkrankung
AT413946B (de) * 2004-07-13 2006-07-15 Mattner Frank Dr Impfstoff gegen die alzheimer-krankheit
CN101137394A (zh) * 2004-10-25 2008-03-05 默克制药公司 抗addl抗体及其应用
WO2006136906A2 (en) * 2005-06-17 2006-12-28 Epfl Ecole Polytechnique Fédérale De Lausanne Switch-peptides as tool for the study of fibrillogenesis
DK2361638T3 (en) * 2005-12-12 2014-03-03 Ac Immune Sa Beta-1-42-specific monoclonal antibodies with therapeutic properties
EP1992639A4 (en) * 2006-02-22 2009-08-26 Hayashibara Biochem Lab PEPTIDE VACCINE FOR INDUCING THE PRODUCTION OF AN ANTIAMYLOID PEPTIDANT BODY

Also Published As

Publication number Publication date
JP2011522840A (ja) 2011-08-04
RU2491953C2 (ru) 2013-09-10
AT509611A1 (de) 2011-10-15
AT509611B1 (de) 2012-04-15
MX2010013657A (es) 2011-04-11
EP2310033A2 (en) 2011-04-20
AT506820B1 (de) 2011-07-15
CN102123728A (zh) 2011-07-13
US8409581B2 (en) 2013-04-02
WO2009149485A3 (en) 2010-06-10
ES2392789T3 (es) 2012-12-13
JP2014139227A (ja) 2014-07-31
JP2015110588A (ja) 2015-06-18
WO2009149485A2 (en) 2009-12-17
JP5989074B2 (ja) 2016-09-07
KR20110036039A (ko) 2011-04-06
US20110171243A1 (en) 2011-07-14
BRPI0915136A2 (pt) 2019-09-24
CA2723967A1 (en) 2009-12-17
IL209894A0 (en) 2011-02-28
IL209894A (en) 2015-08-31
AU2009257168A1 (en) 2009-12-17
CN102123728B (zh) 2017-05-31
JP5984867B2 (ja) 2016-09-06
AT506820A1 (de) 2009-12-15
RU2011100125A (ru) 2012-07-20
AU2009257168B2 (en) 2015-01-22

Similar Documents

Publication Publication Date Title
EP2310033B1 (en) Peptide compounds for treating amyloidoses
EP2310034B9 (en) Peptides for treating beta-amyloidoses
US20130287807A1 (en) Compounds for treating symptoms associated with parkinson's disease
US8828942B2 (en) Means for treating synucleinopathies
HK1152470B (en) Peptides for treating beta-amyloidoses

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110104

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602009009533

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61K0038080000

Ipc: C07K0007060000

Ref country code: HK

Ref legal event code: DE

Ref document number: 1152471

Country of ref document: HK

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 25/28 20060101ALI20120302BHEP

Ipc: A61P 25/16 20060101ALI20120302BHEP

Ipc: A61K 38/08 20060101ALI20120302BHEP

Ipc: C07K 16/18 20060101ALI20120302BHEP

Ipc: C07K 7/06 20060101AFI20120302BHEP

RTI1 Title (correction)

Free format text: PEPTIDE COMPOUNDS FOR TREATING AMYLOIDOSES

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA RS

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 574087

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120915

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602009009533

Country of ref document: DE

Effective date: 20121031

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2392789

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20121213

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121206

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130105

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130107

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121205

26N No opposition filed

Effective date: 20130606

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602009009533

Country of ref document: DE

Effective date: 20130606

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: CH

Ref legal event code: AECN

Free format text: DAS PATENT IST AUFGRUND DES WEITERBEHANDLUNGSANTRAGS VOM 28. FEBRUAR 2014 REAKTIVIERT WORDEN.

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: SPIERENBURG AND PARTNER AG, PATENT- UND MARKEN, CH

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130612

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120905

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20090612

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20150518

Year of fee payment: 7

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160612

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1152471

Country of ref document: HK

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20180619

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20180608

Year of fee payment: 10

Ref country code: IT

Payment date: 20180605

Year of fee payment: 10

Ref country code: BE

Payment date: 20180620

Year of fee payment: 10

Ref country code: FR

Payment date: 20180522

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20180703

Year of fee payment: 10

Ref country code: GB

Payment date: 20180626

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20180731

Year of fee payment: 10

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602009009533

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 574087

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190612

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20190612

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20190630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200101

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190612

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190612

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190612

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190630

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190630

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190630

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20201028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190613